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首页> 外文期刊>Bioorganic and Medicinal Chemistry Letters >Predictive screening model for potential vector-mediated transport of cationic substrates at the blood-brain barrier choline transporter.
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Predictive screening model for potential vector-mediated transport of cationic substrates at the blood-brain barrier choline transporter.

机译：潜在的矢量介导的阳离子底物在血脑屏障胆碱转运蛋白上的转运的预测筛选模型。

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摘要

A set of semi-rigid cyclic and acyclic bis-quaternary ammonium analogs, which were part of a drug discovery program aimed at identifying antagonists at neuronal nicotinic acetylcholine receptors, were investigated to determine structural requirements for affinity at the blood-brain barrier choline transporter (BBB CHT). This transporter may have utility as a drug delivery vector for cationic molecules to access the central nervous system. In the current study, a virtual screening model was developed to aid in rational drug design/ADME of cationic nicotinic antagonists as BBB CHT ligands. Four 3D-QSAR comparative molecular field analysis (CoMFA) models were built which could predict the BBB CHT affinity for a test set with an r(2) <0.5 and cross-validated q(2) of 0.60, suggesting good predictive capability for these models. These models will allow the rapid in silico screening of binding affinity at the BBB CHT of both known nicotinic receptor antagonists and virtual compound libraries with the goal of informing the design of brain bioavailable quaternary ammonium analogs that are high affinity selective nicotinic receptor antagonists.
机译：研究了一组半刚性的环状和非环状的双季铵盐类似物，它们是一项药物开发计划的一部分，该计划旨在确定神经元烟碱乙酰胆碱受体的拮抗剂，以确定对血脑屏障胆碱转运蛋白亲和力的结构要求（ BBB CHT）。该转运蛋白可用作阳离子分子进入中枢神经系统的药物递送载体。在当前的研究中，开发了虚拟筛选模型，以帮助阳离子烟碱类拮抗剂作为BBB CHT配体进行合理的药物设计/ ADME。建立了四个3D-QSAR比较分子场分析（CoMFA）模型，这些模型可以预测r（2）<0.5和交叉验证的q（2）为0.60的测试集的BBB CHT亲和力，从而表明它们具有良好的预测能力楷模。这些模型将允许对已知的烟碱样受体拮抗剂和虚拟化合物文库在BBB CHT上的结合亲和力进行快速的计算机筛选，目的是设计出具有高亲和力的选择性烟碱样受体拮抗剂的脑可生物利用的季铵盐类似物。

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